Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).

Efficacy of a 1:1 ratio VWF/FVIII concentrate in patients with von Willebrand disease.

INTRODUCTION: Patients with von Willebrand disease (VWD) require administration of von Willebrand factor (VWF) concentrates peri-operatively. Concerns about FVIII accumulation after repetitive injections of a 1:1 ratio VWF/FVIII clotting factor concentrate (CFC) led this study to explore the recovery and FVIII accumulation over time. METHODS: This monocentre study examined patients with VWD receiving perioperative 1:1 ratio CFC infusions. CFC dosing was based on body weight and endogenous VWF/FVIII activity. FVIII and VWF activity was monitored at T0 (baseline), T1 (15 min postinfusion), and trough levels at T2-T6 (24-120 h). RESULTS: We included 125 patients, undergoing 125 procedures (63 major surgeries, 62 minor), with a median of two CFC infusions (IQR 1-3). With a mean administered dose of 35.7 IU/kg CFC, recovery rates of FVIII and VWF were 2.6 IU/dL per IU/kg and 2.4 IU/dL per IU/kg, respectively. Mean FVIII levels at T0 were 62 (SD 51.9), T1: 164 (SD 80.4), T2: 155 (SD 62.8), T3: 162 (SD 59.8), T4: 124 (SD 78.4), and T5: 120 (SD 65.3) IU/dL. Mean VWF activity levels at T0 were 29 (SD 25.0), T1: 133 (SD 43.7), T2: 92 (SD 37.2), and T3: 86 (SD 37.5) IU/dL. Subgroup analysis in 47 patients with more than three infusions, showed no accumulation of mean FVIII levels. CONCLUSION: This perioperative study demonstrated excellent FVIII and VWF recovery of a 1:1 ratio VWF product in patients with VWD. Stable FVIII and VWF activity levels were observed after repeated infusions, without accumulation. Most major surgeries required only three CFC infusions.

Correlation of gene expression with magnetic resonance imaging features of retinoblastoma: a multi-center radiogenomics validation study.

OBJECTIVES: To validate associations between MRI features and gene expression profiles in retinoblastoma, thereby evaluating the repeatability of radiogenomics in retinoblastoma. METHODS: In this retrospective multicenter cohort study, retinoblastoma patients with gene expression data and MRI were included. MRI features (scored blinded for clinical data) and matched genome-wide gene expression data were used to perform radiogenomic analysis. Expression data from each center were first separately processed and analyzed. The end product normalized expression values from different sites were subsequently merged by their Z-score to permit cross-sites validation analysis. The MRI features were non-parametrically correlated with expression of photoreceptorness (radiogenomic analysis), a gene expression signature informing on disease progression. Outcomes were compared to outcomes in a previous described cohort. RESULTS: Thirty-six retinoblastoma patients were included, 15 were female (42%), and mean age was 24 (SD 18) months. Similar to the prior evaluation, this validation study showed that low photoreceptorness gene expression was associated with advanced stage imaging features. Validated imaging features associated with low photoreceptorness were multifocality, a tumor encompassing the entire retina or entire globe, and a diffuse growth pattern (all p < 0.05). There were a number of radiogenomic associations that were also not validated. CONCLUSIONS: A part of the radiogenomic associations could not be validated, underlining the importance of validation studies. Nevertheless, cross-center validation of imaging features associated with photoreceptorness gene expression highlighted the capability radiogenomics to non-invasively inform on molecular subtypes in retinoblastoma. CLINICAL RELEVANCE STATEMENT: Radiogenomics may serve as a surrogate for molecular subtyping based on histopathology material in an era of eye-sparing retinoblastoma treatment strategies. KEY POINTS: • Since retinoblastoma is increasingly treated using eye-sparing methods, MRI features informing on molecular subtypes that do not rely on histopathology material are important. • A part of the associations between retinoblastoma MRI features and gene expression profiles (radiogenomics) were validated. • Radiogenomics could be a non-invasive technique providing information on the molecular make-up of retinoblastoma.

MRI Features for Identifying MYCN-amplified RB1 Wild-type Retinoblastoma.

Background MYCN-amplified RB1 wild-type (MYCNARB1+/+) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of MYCNARB1+/+ retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with MYCNARB1+/+ retinoblastoma and age-matched children with RB1-/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing (RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCNARB1+/+ retinoblastoma and 88 control children with RB1-/- retinoblastoma. Children in the MYCNARB1+/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1-/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCNARB1+/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCNARB1+/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCNARB1+/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.

Can motor proficiency testing predict sports injuries and sports-induced bleeds in people with haemophilia?

INTRODUCTION: Predicting the risk of sports injuries and sports-induced bleeds (SIBs) in people with haemophilia (PWH) may support clinical counselling. AIM: To assess the association between motor proficiency testing and sports injuries and SIBs and to identify a specific set of tests for predicting injury risk in PWH. METHODS: In a single centre, prospective study male PWH aged 6-49 playing sports ≥1x/week were tested for running speed and agility, balance, strength and endurance. Test results below -2Z were considered poor. Sports injuries and SIBs were collected for 12 months while 7 days of physical activity (PA) for each season was registered with accelerometers. Injury risk was analysed according to test results and type of physical activity (%time walking, cycling, running). Predictive values for sports injuries and SIBs were determined. RESULTS: Data from 125 PWH (mean [± SD] age: 25 [± 12], 90% haemophilia A; 48% severe, 95% on prophylaxis, median factor level: 2.5 [IQR 0-15]IU/dl) were included. Few participants (n = 19, 15%) had poor scores. Eighty-seven sports injuries and 26 SIBs were reported. Poor scoring participants reported 11/87 sports injuries and 5/26 SIBs. The current tests were poor predictors of sports injuries (Range PPV: 0%-40%), or SIBs (PPV: 0%-20%). PA type was not associated with season (activity seasonal p values > .20) and type of PA was not associated with sports injuries or SIBs (Spearman's rho < .15). CONCLUSION: These motor proficiency- and endurance tests were unable to predict sports injuries or SIBs in PWH, potentially due to few PWH with poor results and low numbers of sports injuries and SIBs.

Liver-related complications before and after successful treatment of chronic hepatitis C virus infection in people with inherited bleeding disorders.

INTRODUCTION: With availability of direct-acting antivirals (DAA), most persons with inherited bleeding disorders are currently cured of hepatitis C virus (HCV) infection. The risk of liver-related complications following HCV cure has not been reported for this population. AIM: Reporting liver-related complications during long-term chronic HCV infection and following sustained virological response (SVR) in this population. METHODS: Retrospective follow-up of a prospective single-centre cohort of HCV antibody-positive persons with inherited bleeding disorders. Primary endpoint was liver-related complications [hepatocellular carcinoma (HCC), decompensated cirrhosis, bleeding gastroesophageal varices]. Liver-related complications were reported separately during chronic HCV and following SVR, stratified for interferon-based and DAA-based SVR. RESULTS: In total 309/381 (81%) HCV antibody-positive individuals developed chronic HCV infection. Median follow-up was 44 years [interquartile range (IQR): 34-50]. Liver-related complications occurred in 36/309 (12%) of individuals with chronic HCV infection after median 31 years of chronic infection. Of 199 individuals with SVR, 97 were cured with interferon-based regimens and 102 with DAA after median infection durations of 29 and 45 years, respectively. At end of follow-up, respectively, 21% and 42% had advanced fibrosis or cirrhosis. Post-SVR, seven (4%) individuals had a liver-related complication, mainly HCC (n = 4). Incidence of liver-related complications per 100 patient-years post-SVR follow-up was .2 for interferon-cured and 1.0 for DAA-cured individuals (p = .01). CONCLUSION: Successful HCV treatment does not eliminate the risk of liver-related complications in persons with inherited bleeding disorders. Due to higher baseline risk, incidence was higher after DAA than interferon-based SVR. We advise continuing HCC surveillance post-SVR in all with advanced fibrosis or cirrhosis.

Clotting factor activity levels and bleeding risk in people with haemophilia playing sports.

BACKGROUND: Improved treatment options for people with haemophilia (PWH) have increased the possibilities for sports participation, but the risk of sports-induced bleeding (SIB) is still considered considerable by many. AIM: To assess sports associated injury- and bleeding risk in PWH and to assess clotting levels associated with safe sports participation. METHODS: Sports injuries and SIBs were prospectively collected for 12 months in PWH aged 6-49 without inhibitors playing sports at least once weekly. Injuries were compared according to factor levels, severity, joint health, sports risk category and sports intensity. Factor activity at the time of injury was estimated using a pharmacokinetic model. RESULTS: 125 participants aged 6-49 (41 children, 90% haemophilia A; 48% severe, 95% severe on prophylaxis) were included. Sports injuries were reported by 51 participants (41%). Most participants (62%) reported no bleeds at all and only 16% reported SIBs. SIBs were associated with factor levels at time of injury (OR: 0.93/%factor level (CI 0.88-0.99); p = .02), but not with haemophilia severity (OR: 0.62 (CI 0.20-1.89); p = .40), joint health, sports risk category or sports intensity. PWH with factor levels <10% during sports injury had a bleeding risk of 41% versus 20% in those with higher (>10%) factor levels. CONCLUSION: The results of this study emphasize the importance of clotting factor levels in prevention of bleeds. This information is vital for patient counselling and tailoring prophylactic treatment with clotting factors and non-replacement therapy.

Transition readiness among adolescents and young adults with haemophilia in the Netherlands: Nationwide questionnaire study.

INTRODUCTION: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement. OBJECTIVE: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs. METHODS: All Dutch adolescents and young adults aged 12-25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple-choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio-demographic and disease-related factors, treatment adherence, health-related quality of life, and self-efficacy. RESULTS: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12-14 year-olds to 63% in 15-17 year-olds. Nearly all post-transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS-Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9-29), compared to those ready for transition (11, IQR 9-16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs. CONCLUSIONS: Nearly all post-transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs.

Optic nerve thickening on high-spatial-resolution MRI predicts early-stage postlaminar optic nerve invasion in retinoblastoma.

OBJECTIVES: To assess the diagnostic accuracy of nerve thickening on MRI to predict early-stage postlaminar optic nerve invasion (PLONI) in retinoblastoma. Furthermore, this study aimed to incorporate measurements into a multiparametric model for radiological determination of PLONI. METHODS: In this retrospective multicenter case-control study, high-spatial-resolution 3D T2-weighted MR images were used to measure the distal optic nerve. Histopathology was the reference standard for PLONI. Two neuroradiologists independently measured the optic nerve width, height, and surface at 0, 3, and 5 mm from the most distal part of the optic nerve. Subsequently, PLONI was scored on contrast-enhanced T1-weighted and 3D T2-weighted images, blinded for clinical data. Optic nerve measurements with the highest diagnostic accuracy for PLONI were incorporated into a prediction model for radiological determination of PLONI. RESULTS: One hundred twenty-four retinoblastoma patients (median age, 22 months [range, 0-113], 58 female) were included, resulting in 25 retinoblastoma eyes with histopathologically proven PLONI and 206 without PLONI. ROC analysis of axial optic nerve width measured at 0 mm yielded the best area under the curve of 0.88 (95% confidence interval: 0.79, 0.96; p < 0.001). The optimal width cutoff was ≥ 2.215 mm, with a sensitivity of 84% (95% CI: 64, 95%) and specificity of 83% (95% CI: 75, 89%) for detecting PLONI. Combining width measurements with the suspicion of PLONI on MRI sequences resulted in a prediction model with an improved sensitivity and specificity of respectively up to 88% and 92%. CONCLUSION: Postlaminar optic nerve thickening can predict early-stage postlaminar optic nerve invasion in retinoblastoma. CLINICAL RELEVANCE STATEMENT: This study provides an additional tool for clinicians to help determine postlaminar optic nerve invasion, which is a risk factor for developing metastatic disease in retinoblastoma patients. KEY POINTS: • The diagnostic accuracy of contrast-enhanced MRI for detecting postlaminar optic nerve invasion is limited in retinoblastoma patients. • Optic nerve thickening can predict postlaminar optic nerve invasion. • A prediction model combining MRI features has a high sensitivity and specificity for detecting postlaminar optic nerve invasion.

Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19.

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Evaluation of Exacerbation and Symptom-Free Time in Patients with COPD.

In clinical practice, clinicians mainly focus on Chronic Obstructive Pulmonary Disease (COPD) exacerbations and symptoms, while patients may prefer to evaluate periods free of COPD exacerbations and deteriorated symptoms. The latter would suit the positive health approach that centralizes people and their beliefs. We aimed to identify patient characteristics and health outcomes relating to: 1) COPD exacerbation-free days; 2) days with no more symptoms than usual; and 3) combined COPD exacerbation and comorbid flare-up-free days (i.e. chronic heart failure, anxiety, depression flare-ups) using negative binomial regression analyzes. Data were obtained from two self-management intervention trials including COPD patients with and without comorbidities. 313 patients (mean age 66.0 years, 63.6% male, 68.7% comorbidity) were included. Better baseline chronic respiratory questionnaire (CRQ) fatigue (incidence rate ratio (IRR) = 1.03 (95% CI 1.01-1.05), p = 0.02) and mastery scores (IRR = 1.03 (95% CI 1.00-1.06), p = 0.04) and fewer courses of antibiotics (IRR = 0.95 (95% CI 0.94-0.96), p < 0.01) were related to more COPD exacerbation-free days. Additionally, better baseline CRQ fatigue (IRR = 1.05 (95% CI 1.00-1.10), p = 0.04) and mastery scores (IRR = 1.06 (95% CI 1.00-1.12), p = 0.04), fewer courses of antibiotics (IRR = 0.94 (95% CI 0.91-0.96), p < 0.01), and improved CRQ dyspnea scores over 12 months of follow-up (IRR = 1.07 (95% CI 1.01-1.12), p < 0.01) were correlated to more days free of deteriorated symptoms. Less baseline dyspnea (modified Medical Research Council score) (IRR = 0.95 (95% CI 0.92-0.98), p < 0.01) and fewer courses of antibiotics (IRR = 0.94 (95% CI 0.93-0.95), p < 0.01) were associated with more combined COPD exacerbation and comorbid flare-up-free days. Healthcare professionals should be aware that less fatigue and better mastering of COPD relate to more exacerbation and symptom-free time in COPD patients.

Immunopathology of the optic nerve in multiple sclerosis.

Optic neuritis, a primary clinical manifestation commonly observed in multiple sclerosis (MS), is a major factor leading to permanent loss of vision. Despite decreased vision (optic neuritis), diplopia, and nystagmus, the immunopathology of the optic nerve in MS is unclear. Here, we have characterized the optic nerve pathology in a large cohort of MS cases (n = 154), focusing on the immune responses in a sub-cohort of MS (n = 30) and control (n = 6) cases. Immunohistochemistry was used to characterize the myeloid (HLA-DR, CD68, Iba1, TMEM119, and P2RY12) and adaptive immune cells (CD4, CD8, and CD138) in the parenchyma, perivascular spaces, and meninges in optic nerve tissues from MS and control cases. Of the 154 MS cases, 122 (79%) reported visual problems; of which, 99 (81%) optic nerves showed evidence of damage. Of the 31 cases with no visual disturbances, 19 (61%) showed evidence of pathology. A pattern of myeloid cell activity and demyelination in the optic nerve was similar to white matter lesions in the brain and spinal cord. In the optic nerves, adaptive immune cells were more abundant in the meninges close to active and chronic active lesions, and significantly higher compared with the parenchyma. Similar to brain tissues in this Dutch cohort, B-cell follicles in the meninges were absent. Our study reveals that optic nerve pathology is a frequent event in MS and may occur in the absence of clinical symptoms.

Magnetic Resonance Imaging Can Reliably Differentiate Optic Nerve Inflammation from Tumor Invasion in Retinoblastoma with Orbital Cellulitis.

PURPOSE: To investigate the prevalence and magnetic resonance imaging (MRI) phenotype of retinoblastoma-associated orbital cellulitis. Additionally, this study aimed to identify postlaminar optic nerve enhancement (PLONE) patterns differentiating between inflammation and tumor invasion. DESIGN: A monocenter cohort study assessed the prevalence of orbital cellulitis features on MRI in retinoblastoma patients. A multicenter case-control study compared MRI features of the retinoblastoma-associated orbital cellulitis cases with retinoblastoma controls. PARTICIPANTS: A consecutive retinoblastoma patient cohort of 236 patients (311 eyes) was retrospectively investigated. Subsequently, 30 retinoblastoma cases with orbital cellulitis were compared with 30 matched retinoblastoma controls without cellulitis. METHODS: In the cohort study, retinoblastoma MRI scans were scored on presence of inflammatory features. In the case-control study, MRI scans were scored on intraocular features and PLONE patterns. Postlaminar enhancement patterns were compared with histopathologic assessment of postlaminar tumor invasion. Interreader agreement was assessed, and exact tests with Bonferroni correction were adopted for statistical comparisons. MAIN OUTCOME MEASURES: Prevalence of retinoblastoma-associated orbital cellulitis on MRI was calculated. Frequency of intraocular MRI features was compared between cases and controls. Sensitivity and specificity of postlaminar optic nerve patterns for detection of postlaminar tumor invasion were assessed. RESULTS: The MRI prevalence of retinoblastoma-associated orbital cellulitis was 6.8% (16/236). Retinoblastoma with orbital cellulitis showed significantly more tumor necrosis, uveal abnormalities (inflammation, hemorrhage, and necrosis), lens luxation (all P < 0.001), and a larger eye size (P = 0.012). The inflammatory pattern of optic nerve enhancement (strong enhancement similar to adjacent choroid) was solely found in orbital cellulitis cases, of which none (0/16) showed tumor invasion on histopathology. Invasive pattern enhancement was found in both cases and controls, of which 50% (5/10) showed tumor invasion on histopathology. Considering these different enhancement patterns suggestive for either inflammation or tumor invasion increased specificity for detection of postlaminar tumor invasion in orbital cellulitis cases from 32% (95% confidence interval [CI], 16-52) to 89% (95% CI, 72-98). CONCLUSIONS: Retinoblastoma cases presenting with orbital cellulitis show MRI findings of a larger eye size, extensive tumor necrosis, uveal abnormalities, and lens luxation. Magnetic resonance imaging contrast-enhancement patterns within the postlaminar optic nerve can differentiate between tumor invasion and inflammatory changes.

ACE2 Protein Expression During Childhood, Adolescence, and Early Adulthood.

Purpose and context. Angiotensin-converting enzyme 2 is the entry receptor for SARS-CoV and SARS-CoV-2. Variations in ACE2 expression might explain age-related symptomatology of COVID-19, that is, more gastro-intestinal symptoms and less pulmonary complaints. This study qualitatively investigated ACE2 protein expression in various organs from the fetal to the young adolescent stage. Method. Autopsy samples from lung, heart, liver, stomach, small intestine, pancreas, kidney, adrenals, and brain (when available) were obtained from twenty subjects aged 24 weeks gestational age through 28 years. Formalin-fixed paraffin-embedded 4-um-thick tissue sections were stained against ACE2. Key results. We showed that the extent of ACE2 expression is age-related. With age, expression increases in lungs and decreases in intestines. In the other examined organs, ACE2 protein expression did not change with age. In brain tissue, ACE2 was expressed in astrocytes and endothelial cells. Conclusions. Age-related ACE2 expression differences could be one substrate of the selective clinical vulnerability of the respiratory and gastro-intestinal system to SARS-CoV-2 infection during infancy.

Self-management interventions for people with chronic obstructive pulmonary disease.

BACKGROUND: Self-management interventions help people with chronic obstructive pulmonary disease (COPD) to acquire and practise the skills they need to carry out disease-specific medical regimens, guide changes in health behaviour and provide emotional support to enable them to control their disease. Since the 2014 update of this review, several studies have been published. OBJECTIVES: Primary objectives To evaluate the effectiveness of COPD self-management interventions compared to usual care in terms of health-related quality of life (HRQoL) and respiratory-related hospital admissions. To evaluate the safety of COPD self-management interventions compared to usual care in terms of respiratory-related mortality and all-cause mortality. Secondary objectives To evaluate the effectiveness of COPD self-management interventions compared to usual care in terms of other health outcomes and healthcare utilisation. To evaluate effective characteristics of COPD self-management interventions. SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, EMBASE, trials registries and the reference lists of included studies up until January 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) and cluster-randomised trials (CRTs) published since 1995. To be eligible for inclusion, self-management interventions had to include at least two intervention components and include an iterative process between participant and healthcare provider(s) in which goals were formulated and feedback was given on self-management actions by the participant. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed trial quality and extracted data. We resolved disagreements by reaching consensus or by involving a third review author. We contacted study authors to obtain additional information and missing outcome data where possible. Primary outcomes were health-related quality of life (HRQoL), number of respiratory-related hospital admissions, respiratory-related mortality, and all-cause mortality. When appropriate, we pooled study results using random-effects modelling meta-analyses. MAIN RESULTS: We included 27 studies involving 6008 participants with COPD. The follow-up time ranged from two-and-a-half to 24 months and the content of the interventions was diverse. Participants' mean age ranged from 57 to 74 years, and the proportion of male participants ranged from 33% to 98%. The post-bronchodilator forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio of participants ranged from 33.6% to 57.0%. The FEV1/FVC ratio is a measure used to diagnose COPD and to determine the severity of the disease. Studies were conducted on four different continents (Europe (n = 15), North America (n = 8), Asia (n = 1), and Oceania (n = 4); with one study conducted in both Europe and Oceania). Self-management interventions likely improve HRQoL, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score (lower score represents better HRQoL) with a mean difference (MD) from usual care of -2.86 points (95% confidence interval (CI) -4.87 to -0.85; 14 studies, 2778 participants; low-quality evidence). The pooled MD of -2.86 did not reach the SGRQ minimal clinically important difference (MCID) of four points. Self-management intervention participants were also at a slightly lower risk for at least one respiratory-related hospital admission (odds ratio (OR) 0.75, 95% CI 0.57 to 0.98; 15 studies, 3263 participants; very low-quality evidence). The number needed to treat to prevent one respiratory-related hospital admission over a mean of 9.75 months' follow-up was 15 (95% CI 8 to 399) for participants with high baseline risk and 26 (95% CI 15 to 677) for participants with low baseline risk. No differences were observed in respiratory-related mortality (risk difference (RD) 0.01, 95% CI -0.02 to 0.04; 8 studies, 1572 participants ; low-quality evidence) and all-cause mortality (RD -0.01, 95% CI -0.03 to 0.01; 24 studies, 5719 participants; low-quality evidence). We graded the evidence to be of 'moderate' to 'very low' quality according to GRADE. All studies had a substantial risk of bias, because of lack of blinding of participants and personnel to the interventions, which is inherently impossible in a self-management intervention. In addition, risk of bias was noticeably increased because of insufficient information regarding a) non-protocol interventions, and b) analyses to estimate the effect of adhering to interventions. Consequently, the highest GRADE evidence score that could be obtained by studies was 'moderate'. AUTHORS' CONCLUSIONS: Self-management interventions for people with COPD are associated with improvements in HRQoL, as measured with the SGRQ, and a lower probability of respiratory-related hospital admissions. No excess respiratory-related and all-cause mortality risks were observed, which strengthens the view that COPD self-management interventions are unlikely to cause harm. By using stricter inclusion criteria, we decreased heterogeneity in studies, but also reduced the number of included studies and therefore our capacity to conduct subgroup analyses. Data were therefore still insufficient to reach clear conclusions about effective (intervention) characteristics of COPD self-management interventions. As tailoring of COPD self-management interventions to individuals is desirable, heterogeneity is and will likely remain present in self-management interventions. For future studies, we would urge using only COPD self-management interventions that include iterative interactions between participants and healthcare professionals who are competent using behavioural change techniques (BCTs) to elicit participants' motivation, confidence and competence to positively adapt their health behaviour(s) and develop skills to better manage their disease. In addition, to inform further subgroup and meta-regression analyses and to provide stronger conclusions regarding effective COPD self-management interventions, there is a need for more homogeneity in outcome measures. More attention should be paid to behavioural outcome measures and to providing more detailed, uniform and transparently reported data on self-management intervention components and BCTs. Assessment of outcomes over the long term is also recommended to capture changes in people's behaviour. Finally, information regarding non-protocol interventions as well as analyses to estimate the effect of adhering to interventions should be included to increase the quality of evidence.

Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain.

To monitor innate immune responses in the CNS, the 18 kDa Translocator protein (TSPO) is a frequently used target for PET imaging. The frequent assumption that increased TSPO expression in the human CNS reflects pro-inflammatory activation of microglia has been extrapolated from rodent studies. However, TSPO expression does not increase in activated human microglia in vitro. Studies of multiple sclerosis (MS) lesions reveal that TSPO is not restricted to pro-inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia. Here, we investigated quantitative relationships between TSPO expression and microglia/macrophage phenotypes in white matter and lesions of brains with MS pathology. In white matter from brains with no disease pathology, normal appearing white matter (NAWM), active MS lesions and chronic active lesion rims, over 95% of TSPO+ cells are microglia/macrophages. Homeostatic microglial markers in NAWM and control tissue are lost/reduced in active lesions and chronic active lesion rims, reflecting cell activation. Nevertheless, pixel analysis of TSPO+ cells (n = 12,225) revealed that TSPO expression per cell is no higher in active lesions and chronic active lesion rims (where myeloid cells are activated) relative to NAWM and control. This data suggests that whilst almost all the TSPO signal in active lesions, chronic active lesion rims, NAWM and control is associated with microglia/macrophages, their TSPO expression predominantly reflects cell density and not activation phenotype. This finding has implications for the interpretation of TSPO PET signal in MS and other CNS diseases, and further demonstrates the limitation of extrapolating TSPO biology from rodents to humans.

Cuprizone-induced demyelination triggers a CD8-pronounced T cell recruitment.

The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone-intoxicated mice and post-mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro-inflammatory milieu in the CNS of cuprizone-intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone-intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone-induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.

COVID-19: Histopathological correlates of imaging patterns on chest computed tomography.

BACKGROUND AND OBJECTIVE: Patients with coronavirus disease 2019 (COVID-19) pneumonia present with typical findings on chest computed tomography (CT), but the underlying histopathological patterns are unknown. Through direct regional correlation of imaging findings to histopathological patterns, this study aimed to explain typical COVID-19 CT patterns at tissue level. METHODS: Eight autopsy cases were prospectively selected of patients with PCR-proven COVID-19 pneumonia with varying clinical manifestations and causes of death. All had been subjected to chest CT imaging 24-72 h prior to death. Twenty-seven lung areas with typical COVID-19 patterns and two radiologically unaffected pulmonary areas were correlated to histopathological findings in the same lung regions. RESULTS: Two dominant radiological patterns were observed: ground-glass opacity (GGO) (n = 11) and consolidation (n = 16). In seven of 11 sampled areas of GGO, diffuse alveolar damage (DAD) was observed. In four areas of GGO, the histological pattern was vascular damage and thrombosis, with (n = 2) or without DAD (n = 2). DAD was also observed in five of 16 samples derived from areas of radiological consolidation. Seven areas of consolidation were based on a combination of DAD, vascular damage and thrombosis. In four areas of consolidation, bronchopneumonia was found. Unexpectedly, in samples from radiologically unaffected lung parenchyma, evidence was found of vascular damage and thrombosis. CONCLUSION: In COVID-19, radiological findings of GGO and consolidation are mostly explained by DAD or a combination of DAD and vascular damage plus thrombosis. However, the different typical CT patterns in COVID-19 are not related to specific histopathological patterns. Microvascular damage and thrombosis are even encountered in the radiologically normal lung.

A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis.

The 18 kDa translocator protein (TSPO) is increasingly used to study brain and spinal cord inflammation in degenerative diseases of the CNS such as multiple sclerosis. The enhanced TSPO PET signal that arises during disease is widely considered to reflect activated pathogenic microglia, although quantitative neuropathological data to support this interpretation have not been available. With the increasing interest in the role of chronic microglial activation in multiple sclerosis, characterising the cellular neuropathology associated with TSPO expression is of clear importance for understanding the cellular and pathological processes on which TSPO PET imaging is reporting. Here we have studied the cellular expression of TSPO and specific binding of two TSPO targeting radioligands (3H-PK11195 and 3H-PBR28) in tissue sections from 42 multiple sclerosis cases and 12 age-matched controls. Markers of homeostatic and reactive microglia, astrocytes, and lymphocytes were used to investigate the phenotypes of cells expressing TSPO. There was an approximate 20-fold increase in cells double positive for TSPO and HLA-DR in active lesions and in the rim of chronic active lesion, relative to normal appearing white matter. TSPO was uniformly expressed across myeloid cells irrespective of their phenotype, rather than being preferentially associated with pro-inflammatory microglia or macrophages. TSPO+ astrocytes were increased up to 7-fold compared to normal-appearing white matter across all lesion subtypes and accounted for 25% of the TSPO+ cells in these lesions. To relate TSPO protein expression to ligand binding, specific binding of the TSPO ligands 3H-PK11195 and 3H-PBR28 was determined in the same lesions. TSPO radioligand binding was increased up to seven times for 3H-PBR28 and up to two times for 3H-PK11195 in active lesions and the centre of chronic active lesions and a strong correlation was found between the radioligand binding signal for both tracers and the number of TSPO+ cells across all of the tissues examined. In summary, in multiple sclerosis, TSPO expression arises from microglia of different phenotypes, rather than being restricted to microglia which express classical pro-inflammatory markers. While the majority of cells expressing TSPO in active lesions or chronic active rims are microglia/macrophages, our findings also emphasize the significant contribution of activated astrocytes, as well as smaller contributions from endothelial cells. These observations establish a quantitative framework for interpretation of TSPO in multiple sclerosis and highlight the need for neuropathological characterization of TSPO expression for the interpretation of TSPO PET in other neurodegenerative disorders.

CRP-guided antibiotic treatment in acute exacerbations of COPD in hospital admissions.

The role of antibiotics in acute exacerbations of chronic obstructive pulmonary disease (COPD) is controversial and a biomarker identifying patients who benefit from antibiotics is mandatory. We performed a randomised, controlled trial in patients with acute exacerbations of COPD, comparing C-reactive protein (CRP)-guided antibiotic treatment to patient reported symptoms in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, in order to show a reduction in antibiotic prescription.Patients hospitalised with acute exacerbations of COPD were randomised to receive antibiotics based either on the GOLD strategy or according to the CRP strategy (CRP ≥50 mg·L-1).In total, 101 patients were randomised to the CRP group and 119 to the GOLD group. Fewer patients in the CRP group were treated with antibiotics compared to the GOLD group (31.7% versus 46.2%, p=0.028; adjusted odds ratio (OR) 0.178, 95% CI 0.077-0.411, p=0.029). The 30-day treatment failure rate was nearly equal (44.5% in the CRP group versus 45.5% in the GOLD-group, p=0.881; adjusted OR 1.146, 95% CI 0.649-1.187, p=0.630), as was the time to next exacerbation (32 days in the CRP group versus 28 days in the GOLD group, p=0.713; adjusted hazard ratio 0.878, 95% CI 0.649-1.187, p=0.398). Length of stay was similar in both groups (7 days in the CRP group versus 6 days in the GOLD group, p=0.206). On day-30, no difference in symptom score, quality of life or serious adverse events was detected.Use of CRP as a biomarker to guide antibiotic treatment in severe acute exacerbations of COPD leads to a significant reduction in antibiotic treatment. In the present study, no differences in adverse events between both groups were found. Further research is needed for the generalisability of these findings.